Breast cancer is a common and devastating form of cancer, affecting millions of women per year throughout the world. Many breast tumors are estrogen sensitive and frequently treatable with compounds that interfere with estrogen binding to estrogen receptors (ERs) expressed on the breast tumor tissue. Detecting the level of ER expression and sensitivity to estrogen stimulation is useful for determining that antihormone-type chemotherapy may succeed in a particular patient.
The overexpression of estrogen-inducible genes, pLIV-1 and pLIV2 (also designated pS2), occurs in some breast tumors which also express the estrogen receptor, (Manning D. L. et al. European J. Cancer 29A(10): 1462-1468 (1993): Manning. D. L. et al., European J. Cancer 30A(5):675-678 (1994); Manning. D. L. et al. Acta Oncologica 34 (5):641-646 (1995); Manning, D. L. et al., U.S. Pat. No. 5,693,465). Expression of pLIV-1, but not pS2, is associated with metastasis of breast cancer cells to regional lymph nodes (Manning et al. U.S. Pat. No. 5,692,465).
In addition, the pathogenesis of various human malignancies, including breast cancer, is affected by proto-oncogenes that encode growth factors and growth factor receptors. Human ErbB2 gene (erbB2, also known as her2, or c-erbB-2), which encodes a 185-kd transmembrane glycoprotein receptor (ErbB2, also known as HER2 or p185HER2) related to the epidermal growth factor receptor (EGFR), is overexpressed in about 25% to 30% of human breast cancer (Slamon et al., Science 235:177-182 [1987]: Slamon et al. Science 244:707-712 [1989]).
Several lines of evidence support a direct role for ErbB2 in the pathogenesis and clinical aggressiveness of ErbB2-overexpressing tumors. The introduction of ErbB2 into non-neoplastic cells causes their malignant transformation (Hudziak et al. Proc. Natl. Acad. Sci. USA 84:7159-7163 [1987]; DiFiore et al., Science 237:78-182 [1987]). Transgenic mice that express ErbB2 develop mammary tumors (Guy et al., Proc. Natl. Acad. Sci. USA 89:10578-10582 [1992]). ErbB2 overexpression is commonly regarded as a predictor of a poor prognosis in humans, especially in patients with primary disease that involves axillary lymph nodes (Slamon et al. [1987] and [1989], supra: Ravdin and Chamness, Gene 159:19-27 [1995]; and Hynes and Stern, Biochim Biophys Acta 1198:165-184 [1994]).
Antibodies directed against human erbB2 protein products (anti-ErbB2 antibodies) and against proteins encoded by the rat equivalent of the erbB2 gene (neu) (anti-neu protein antibodies) down-modulate cell surface expression of p185 on B104-1-1 cells (NIH-3T3 cells transfected with the neu proto-oncogene) and inhibit colony formation of these cells, Drebin et al., Cell 41:695-706 (1985). Biological effects of anti-neu protein antibodies are reviewed in Myers et al., Meth. Enzym. 198:277-290 (1991). See also WO94/22478 published Oct. 13, 1994.
The anti-ErbB2 antibody, 4D5, exhibited anti proliferative effects on the SKDR3 human breast tumor cell line, inhibiting cellular proliferation by approximately 56%, and sensitizing p185erbB2 -overexpressing breast tumor cell lines to the cytotoxic effects of TNF-α. See Hudziak et al., Mol. Cell. Biol. 9(3):1165-1172(1989). See also WO89/06692 published Jul. 27, 1989. The anti-ErbB2 antibodies discussed in Hudziak et al. are further characterized in Fendly et al. Cancer Research 50:1550-1558 (1990); Kotts et al. In Vitro 26(3):59A (1990): Sarup et al. Growth Regulation 1:72-82 (1991): Shepard et al. J. Clin. Immunol. 11(3): 117-127 (1991): Kumar et al. Mol. Cell. Biol. 11(2):979-986 (1991); Lewis et al. Cancer Immunol. Immunother. 37:255-263 (1993); Pietras et al. Oncogene 9:1829-1838 (1994); Vitetta et al. Cancer Research 54:5301-5309 (1994); Sliwkowski et al. J. Biol. Chem. 269(20):14661-14665 (1994): Scott et al. J. Biol. Chem. 266:14300-5 (1991); and D'souza et al. Proc. Natl. Acad. Sci. 91:7202-7206 (1994).
ErbB2 overexpression is also linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoruracil) and anthracyclines (Baselga et al., Oncology 11(3 Suppl 1):43-48 [1997]). Despite the association of ErbB2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to treatment with taxanes were greater than three times those of HER2-negative patients (Ibid), rhuMab HER2 was shown to enhance the activity of paclitaxel (TAXOL®) and doxorubicin against breast cancer xenografts in nude mice injected with BT-474 human breast adenocarcinoma cells, which express high levels of HER2 (Baselga et al. Breast Cancer, Proceedings of ASCO, Vol. 13. Abstract 53 [1994]).
Because breast and other cancers pose constant threats to health, there is a continuing need to develop treatments for cancers by using methods that target cancer cells without simultaneously harming large numbers of non-cancerous cells, thereby limiting adverse side effects associated with traditional cancer chemotherapy.